The commonly used method of oral contraception in human females consists of a combination of estrogen and progestin (progestational agent) administered daily for 21 days. Menstruation occurs about 3 to 5 days after withdrawal and administration is reinitiated after 8 days, thereby beginning a new cycle. Inhibition of ovulation is believed to be the primary mechanism of this contraceptive method. Rudel, et al., Fertility and Sterility, 16, 158-169 (1965) pointed out, however, that progestins, in addition to their antiovulatory action, have other antifertility effects including the production of a state of maturation of the endometrium which is out of phase with ovulation, accompanied by changes in the cervical mucus, these changes being incompatible with vital and motile spermatozoa. The authors suggested that, in an oral contraceptive agent comprising a combination of progestin and estrogen, these other effects (in addition to inhibiting ovulation) of progestins may be lost in the presence of estrogen. Martinez-Manaoutou, et al., ibid, 17, 49- 57 (1966) has also suggested that a low dose of a progestin, specifically chlormadinone acetate, would prevent conception when administered continuously at the rate of 0.5 mg. per day to human females during the entire ovulatory cycle. It was determined that ovulation probably occurred in 60 percent of the patients. Only one pregnancy occurred in 416 patients and 1600 menstrual cycles. From these observations, the authors advocated the continuous administration of minimal doses of a progestin as a contraceptive method in human females. The same laboratory reported, ibid, 17, 57-62 (1967) that chlormadinone acetate, when administered to human females at a dosage of less than 500 mcg. daily, demonstrated antiestrogenic influence on the cervical mucus without suppression of endometrial development. The contraceptive effectiveness of the administered progestational agent appeared to parallel closely the changes in the cervical mucus. The same research group ibid, 18, 219-221 (1967) repeated their previous findings that a progestin, given at dose levels which do not inhibit ovulation, is able to create a state of hormonal inbalance as evidenced by a suppressed endometrium and/or a thickened, scanty cervical mucus. The daily low level administration of a progestin throughout the menstrual cycle was the contraceptive method advocated by the authors for human population control on a large scale. For this purpose, they specifically advocated the employment of an implanted pellet which would meter out the progestin for a month or six weeks.
In summary, the research group headed by Martinez-Manaoutou has found that the low daily dosage of chlormadinone acetate (0.5 mg. daily) throughout the menstrual cycle affords an effective contraceptive method.
U.S. Pat. No. 3,758,687, issued Sept. 11, 1973, discloses the administration to a female human at some point during the interval from the 5th to the 8th day of the menstrual cycle of an amount of a progestin sufficient to prevent conception during the remainder of the cycle. The patented process contemplates the administration of a single dose sufficient to last an entire cycle as an improvement over administration of daily low doses.
A relationship between the progestational state of the uterus and implantation was reported originally by Corner and Allen, Am. J. Physiol., 86, 74 (1928), 88, 340 (1929). The necessity of pretreatment with the follicular hormone (estrogen) for optimal response to the luteal hormone (progesterone) was later observed by many others including Allen, Am. J. Physiol., 92, 612 (1930) and Hisaw and Leonard, Am. J. Physiol., 92, 574 (1930). The phenomenon of sequential influence of ovarian steriods is now widely accepted by research workers studying mammalian reproductive cycles and two phases (follicular and luteal) are recognized.
Estrogen priming is, however, apparently not indispensable for a progestational response, but priming lowers the threshold for uterine responses, including progestational proliferation, increased carbonic anhydrase, [Pincus et al. Endocr., 61, 528 (1957)], and synthesis of DNA and mitosis, [Lee and Dukelow, J. Reprod. Fert., 31 473 (1972)]. Rudel, et al., J. Reprod. Fert., 8, 305 (1964), observed that the progestational response to chlormadinone acetate, a typical progestin, in humans is directly related to the degree of estrogen stimulation of the endometrium at the time treatment is started.
Black, Fertil. Steril., 25, 575 (1974), found that administration of progestins in the proliferative phase of the menstrual cycle altered the progestational state of the endometrium in the luteal phase of the cycle, but continuous treatment nullified the effect. Black suggested that a novel contraceptive method might involve the administration of a progestin, preferably at low dosage levels, to the female mammal only during the proliferative phase of the cycle.
Moghissi et al., writing in Obstetrics and Gynecology, 41, 585 (1973), discussed the mechanism whereby a micro dose of a progestin, norethindrone, administered daily for 30 days prevented conception. The authors found that at least three different factors were involved: alternation of ovulation and progesterone production by the corpus luteum, cervical mucus changes and inhibition of sperm transport, and endometrium changes.
McDonald and coworkers, writing in J. Obstet, Gynaec. Brit. Cwlth., 75, 1123 (1968), discuss results obtained with a progestin tablet in which the progestin is chlormadinone acetate, the progestin acting as an oral contraceptive. The amount of chlormadinone acetate used was 0.5 mg. (500mcg.) daily. It was the authors' opinion that the continous low dose administration of a progestin throughout the menstrual cycle had advantages over the usual oral contraceptive dosage regimen.
Nygren et al., writing in Contraception, 9, 249 (1974), disclosed the contraceptive efficacy of 10 and 25 mgs. norethindrone administered post-ovulatory to human females.
Sakiz, et al. Hormonal Steroids, Proceedings of the Third International Congress, Hambrug, September, 1970 (Excerpta Medica International Congress Series No. 219), pages 865-871, compared the hormonal properties of a new compound, R2323 (13-ethyl-17.alpha.-ethynyl-17.beta.-hydroxy-gona-4,9,11-trien-3-one) with norgestrienone, its 13-methyl homolog, with norethindrone (17.alpha. -ethynyl-19-nortestosterone) and with norgestrel, the 13-ethyl homolog of norethindrone. A further study of the antifertility effects of this new compound is provided by Sakiz et al., Contraception, 10, 467 (1974).
Four contraceptive regimens have recently been patented. Kincl, U.S. Pat. No. 3,822,355, advocates employing a regimen in which a placebo is administered to the female beginning with the first day of menstruation for 16 days and then following ovulation, a progestional agent is administered for the next four days. The dosage is said to be sufficient to inhibit the function of the corpus luteum. The remaining days of the cycle, the patient receives from 10 to 40 percent of the previous progastational agent dosage. Rudel and Kincl, U.S. Pat. No. 3,836,651, advocate administering to a female starting on the fifth day of the menstrual cycle and continuing for 20 to 21 days thereafter a single daily dose of an estrogen and a progestational agent, the estrogen dosage being extremely low. Rochefort, U.S. Pat. No. 3,795,734, advocates a regimen in which consecutive daily doses of a progestin are given during the early phase of the cycle followed by consecutive daily dose of an estrogen-progestin combination during mid-cycle and in the final phase of the cycle a progestin only.
Presently approved oral contraceptive regimens which have been employed either in the United States or overseas include the most widely used procedure involving the use of a combination of progestin and estrogen during 20-21 days of a sexual cycle. This regimen has been implicated in production of an increased incidence of thrombosis. A "minipill" regimen has been tried in which the quantities of progestin and estrogen are greatly reduced from those originally employed, but the same hormones are administered during the menstrual cycle. A second "minipill" regimen involves the use of the progestin only in very small daily doses. This latter regimen may avoid the thrombosis problem associated with estrogen administration but suffers from other side effects particularly including irregular bleeding and also from lowered efficacy. Most of the current research effort in this area is devoted to finding contraceptive regimens using much lower hormonal doses and avoiding administration of an estrogen entirely.
Edgren et al., writing in Fertility and Sterility, 18, 238 (1967), categorized progestational agents in five classes. Several biological tests for determining the properties of each progestational agent with a view to classifying the agent are set forth in this article. Black and Kraay, J. Steroid Biochem., 4, 467 (1973), divide progestational agents into two classes, A and B, depending upon their ability to interact with uterine cytoplasmic receptor sites for estrogen. Their test is based upon the ability of a progestational agent to act as an anti-estrogenic substance by its direct effect on the binding of tritiated estradiol with uterine cytoplasmic receptors, and it was observed by the authors that tritiated estradiol uptake was inhibited by compounds which interacted with the receptors (type A). Type B progestational agents, on the other hand, did not interact with these uterine cytoplasmic receptor sites and, apparently, derived their antiestrogenic effects (characteristic of all progestins) by a different process.
It is an object of this invention to provide an oral contraceptive method which avoids the adverse effects associated with currently employed or suggested contraceptive procedures but which also provides a satisfactorily low pregnancy rate.